1. Field of the Invention
The present invention relates generally to the fields of radioimaging, radiotherapy, labeling, chemotherapy, and chemical synthesis. More particularly, the invention concerns certain novel compounds suitable for single or multimodality imaging, radiochemotherapy, and therapy of hyperproliferative disorders. The compounds are of the general structure X1—Y—X2, wherein Y comprises two or more carbohydrate residues covalently attached to one another to form a carbohydrate backbone, and X1 and X2 are diagnostic or therapeutic moieties covalently attached to Y, provided that when Y does not comprise a glucosamine residue, X1 and X2 are diagnostic moieties. The present invention also concerns methods of synthesis of these compounds and kits for preparing these compounds.
2. Description of Related Art
Biomedical imaging includes various modalities that are widely used by physicians and researchers to assist with not only the diagnosis of disease in a subject, but also to gain a greater understanding of normal structure and function of the body.
One such imaging modality that has been widely used is computerized tomography (CT). CT, developed in the 1970's, was the first imaging modality which marked a substantial improvement in medical imaging technology. By taking a series of X-rays, sometimes more than a thousand, from various angles and then combining them with a computer, CT made it possible to build up a three-dimensional image of any part of the body. Physicians could then instruct the computer to display two-dimensional slices from any angle and at any depth.
In CT, intravenous injection of a radiopaque contrast agent can assist in identifying a suspected soft tissue mass when initial CT scans are not diagnostic. Similarly, contrast agents aid in assessing the vascularity of a soft tissue or bone lesion. For example, the use of contrast agents may allow delineation of the relationship of a tumor and adjacent vascular structures.
In the early 1980s, CT was joined by magnetic resonance imaging (MRI), a clinical diagnostic and research procedure that uses a high-strength magnet and radio-frequency signals to produce images. The most abundant molecular species in biological tissues is water. It is the quantum mechanical “spin” of the water proton nuclei that ultimately gives rise to the signal in imaging experiments. In MRI, the sample to be imaged is placed in a strong static magnetic field (1-12 Tesla) and the spins are excited with a pulse of radio frequency (RF) radiation to produce a net magnetization in the sample. Various magnetic field gradients and other RF pulses then act on the spins to code spatial information into the recorded signals. By collecting and analyzing these signals, it is possible to compute a three-dimensional image which, like a CT image, is normally displayed in two-dimensional slices.
Contrast agents used in MR imaging differ from those used in other imaging techniques. Their purpose is to aid in distinguishing between tissue components with identical signal characteristics and to shorten the relaxation times (which will produce a stronger signal on T1-weighted spin-echo MR images and a less intense signal on T2-weighted images. Examples of MRI contrast agents include gadolinium chelates, manganese chelates, chromium chelates, and iron particles. Although CT and MRI are useful in providing anatomical localization of lesions, the contrast media for these imaging modalities does not provide cellular target information.
Imaging modalities that provide information pertaining to information at the cellular level, such as cellular viability, include positron emission tomography (PET) and single-photon emission computed tomography (SPECT). In PET, a patient ingests or is injected with a slightly radioactive substance that emits positrons, which can be monitored as the substance moves through the body. In one common application, for instance, patients are given glucose with positron emitters attached, and their brains are monitored as they perform various tasks. Since the brain uses glucose as it works, a PET image shows where brain activity is high. Closely related to PET is single-photon emission computed tomography, or SPECT. The major difference between the two is that instead of a positron-emitting substance, SPECT uses a radioactive tracer that emits high-energy photons. SPECT is valuable for diagnosing coronary artery disease, and already some 2.5 million SPECT heart studies are done in the United States each year.
Optical imaging is another imaging modality that has gained widespread acceptance in particular areas of medicine. Examples include fluorescein angiography and indocyanine green angiography.
Another biomedical imaging modality that has gained widespread acceptance is ultrasound. Ultrasound imaging has been used noninvasively to provide realtime cross-sectional and even three-dimensional images of soft tissue structures and blood flow information in the body. High-frequency sound waves and a computer to create images of blood vessels, tissues, and organs.
Ultrasound imaging of blood flow can be limited by a number of factors such as size and depth of the blood vessel. Ultrasonic contrast agents, a relatively recent development, include perfluorinated contrast agents, which are designed to overcome these limitations by helping to enhance grey-scale images and Doppler signals (Deng and Lizzi, 2002; Ophir and Parker, 1989; Goldberg et al., 1994; Goldberg, 1997; Forsberg, 1997).
The combination of more than one imaging modality can allow for the simultaneous acquisition of anatomical information and cellular information, thus allowing for improved resolution of a lesion of interest. Therefore, dual agents can be of particular value in the imaging of tumors. Furthermore, these agents also have the potential to reduce cost and lessen patient inconvenience. The patient would avoid the need to be injected twice. There may be cost savings to the patient because a single study using a dual imaging agent may be less expensive than two separate studies. Furthermore, the patient would save time because it would be expected that two studies using a dual imaging agent would take less time than two separate imaging studies using two different imaging agents.
Therefore, there is a need for a “dual” imaging agents that can be applied in the performance of more than one imaging modality. Description of any agent for use in dual imaging is very limited. See, e.g., U.S. Pat. No. 6,521,209 describing certain optically active magnetic resonance imaging agents, U.S. Pat. No. 6,770,259 pertaining to certain compositions that comprise a radiolabeled LTB4 binding agent and a radiolabeled perfusion imaging agent, and WO 2004/026344, describing agents that include a fluorescent dye and an MRI contrast agent. Thus, there is a need for novel imaging agents that can be used in concurrent imaging using more than one imaging modality.
Furthermore, in view of the epidemiological significance of cancer, there is the need for improved treatments. Chemotherapy and radiotherapy are treatment modalities that are commonly applied in the treatment of cancer. Compounds that can be administered to a subject that can provide for dual chemotherapy and radiation therapy (“radiochemotherapy”) would provide a therapeutic advantage in terms of the dual targeting of a tumor following a single administration, and would also have other potential benefits such as greater patient convenience compared to standard treatment that would involve the application of two separate therapeutic modalities.